Co-Targeting the mTOR and MAPK Pathways is Effective in a Novel Mouse Model of Malignant Peripheral Nerve Sheath Tumors

Abstract

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are soft tissue sarcomas with low 5-year survival rates and no targeted therapies available. Data suggest that the mTOR and MAPK pathways may be involved in the formation and progression of MPNSTs, and both of these pathways can be inhibited with drugs that are currently in use for other tumor types. In vitro, RAD001 and PD-901, inhibitors of the mTOR and MAPK pathways, respectively, are effective at inhibiting proliferation of human MPNST cells, while having little effect on normal human Schwann cells. To better study their therapeutic potential, we tested these drugs in a mouse model of MPNSTs. This model closely resembles genetic changes (Pten loss, EGFR overexpression) and histological feature of human MPNSTs. RAD001 or PD-901 treatment moderately reduced tumor burden and size, and extended lifespan in this model. However, when one pathway is inhibited, there is an increase in signaling through the other pathway, suggesting that these pathways feedback on one another, and that targeting both pathways in combination may be more effective. We found synergistic effects on reducing tumor burden and size, and a significant increase in lifespan when RAD001 and PD-901 are given in combination. The synergy seen is due to the combination therapy allowing for persistent and prolonged reduction in signaling through both pathways, without a subsequent increase in signaling through one pathway, as seen in single agent treatments. These data suggest that co-targeting the mTOR and MAPK pathways could potentially be an effective treatment for patients with MPNSTs.